The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)-induced gamma-activating factor-mediated immunity and interferon alpha (IFNA)-induced interferon-stimulated genes factor 3-mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor-mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3-mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding.

译文

转录因子信号转导子和转录激活因子1(STAT1)在抵抗分枝杆菌和病毒感染的免疫中起着关键作用。在这里,我们表征了来自其他健康的分枝杆菌病患者的三个人STAT1种系等位基因。像新的Q463H和E320Q等位基因一样,先前报道的L706S对干扰素γ(IFNG)诱导的γ激活因子介导的免疫和干扰素α(IFNA)诱导的干扰素刺激的基因因子3介导的免疫都具有内在的危害,如用相应等位基因转染的STAT1缺陷细胞所示。然而,它们的表型作用是由不同的分子机制介导的,L706S影响STAT1磷酸化,Q463H和E320Q影响STAT1 DNA结合活性。杂合子患者表现出特别受损的IFNG诱导的γ活化因子介导的免疫力,导致对分枝杆菌的易感性。确实,IFNA诱导的干扰素刺激基因因子3介导的免疫性没有受到影响,并且这些患者对病毒性疾病特别不敏感,这与两种表型均隐性的其他同样有害的STAT1突变的患者不同。因此,在细胞和临床水平上,这三个STAT1等位基因在IFNG介导的抗分枝杆菌免疫中占主导地位,而在IFNA介导的抗病毒免疫中却处于隐性地位。这些STAT1等位基因定义了两种主要形式的STAT1缺陷,具体取决于突变是否损害STAT1磷酸化或DNA结合。

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